The overall objective of this Program Project is to identify and refine strategies for the prevention and management of dengue. Dengue continues to be an expanding public health problem, disproportionally affecting resource-poor countries in tropical and subtropical regions. Although morbidity from clinically mild infections is still considerable, the principal challenge presented by dengue virus is its ability to cause dengue hemorrhagic fever (DHF), a potentially fatal plasma leakage syndrome. There is no specific therapy or vaccine available against dengue, and development of treatments or vaccines has been problematic because of the evidence that DHF is immunologically mediated. In this application, an experienced interdisciplinary team of university, military, and industry investigators in the US and Thailand proposes to conduct coordinated studies to a) advance understanding of DHF epidemiology, pathophysiology, and immunopathogenesis and b) use this knowledge to identify and validate approaches to management and prevention of dengue disease. Project 1 (Clinical Studies) will involve a prospective study in Bangkok of symptomatic children hospitalized with acute dengue illness, to define the pathophysiology of severe dengue and improve the evaluation and triage of cases, and a prospective population-based study of dengue transmission and disease in Kamphaeng Phet province, to take place concurrently with a phase lib vaccine efficacy trial, to define optimal methods for evaluation of vaccine efficacy and identify correlates of protective immunity. Project 2 (Molecular Immunopathogenesis) will involve detailed laboratory studies of innate and adaptive immune responses to dengue in vitro and in vivo to define the immunologic mechanisms underlying protection and disease pathogenesis. A Clinical Laboratory Core and an Administrative Core will support both Projects. Close interactions and sharing of data between these Projects and Cores will ensure the maximum yield from these research studies, with broad basic science as well as clinical and public health implications.